PL169796B1 - Method of obtaining novel derivatives of methyleobisphosphonic acid - Google Patents

Abstract

Bisphosphonic acid derivs. of formula (I) and their geometrical, optically active isomers and salts are new. In (I), R1, R2, R3 and R4 = opt. unsubstd. 1-10C alkyl or 3-10C cycloalkyl, aryl, aralkyl, silyl (SiR3) or H; where at least one of R1, R2, R3 and R4 is H and at least one is other than H; Q1 = H, OH, halo, NH2, or OR; where R' = 1-4C alkyl or acyl; Q2 = gp. of formula (i); Y = opt. substd. or opt. saturated or aromatic 6 membered heterocyclic gp. or carboxylic aromatic gp., where heterocycle contains 1-3 atoms from N, O and S; X = a bond, O, S or NR"; R" = H, 1-4C lower alkyl or acyl; n = 0 to 6; R' and R" = H, 1-4C lower alkyl. Specifically claimed are 17 cpds. including (((6-methyl -2-pyridinyl)amino) methylidene)bisphosphonic acid P,P'-diethyl ester.

Description

The present invention relates to a process for the preparation of new methylene carbon substituted methylene bisphosphonic acid derivatives, in particular new methylene carbon substituted acid ester and ester of bisphosphonic acid salts. These compounds find use in pharmaceuticals.

Several publications disclose methylenebisphosphonic acids, their salts or some tetraesters, but there are few disclosures of suitable partial esters, tri-, di-, and monoesters.

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In US patents US US 4,447,256 and German 2,831,578 disclose a process for the preparation of certain pyridylaminomethylene bisphosphonic acid tetraethyl esters. According to these patents, the compounds can be used as herbicides, however no disclosure of the pharmaceutical effect of these compounds has been found.

European Patent Specification 337,706 discloses the preparation of such cyclyl- and heterocyclyl-substituted methylenebisphosphonic acid tetraesters in which the ring substituent is either partially or fully saturated.

European Patent No. 282230 discloses the preparation of certain isoxazolyl substituted tetraethyl esters of aminomethylene bisphosphonic acid as well as the preparation of two partial esters.

European Patent No. 298553 discloses the preparation of methylene carbon-substituted methylene phosphonoalkyl phosphates.

The preparation of methylenebisphosphonic acid tetraesters is also described in the publications: J. Am. Chem. Soc. 78, (1956) 4450; J. Am. Chem. Soc. (1959) 2272; J. Am. Chem. Soc. 84 (1962) 1876; J. Org. Chem. 35, (1970) 3149; J. Org. Chem. 36, (1971) 3843, Phosphorus, Sulfur and Silicon 42, (1989), European Patent Application No. 221611.

U.S. Patent Specification US US 3,957,858 relates to a group of compounds primarily in the form of tetraesters and tetraacids intended for water treatment. This use is completely different from the use of the compounds obtained according to the present invention. The compounds of the invention are used to treat bone.

It has now been found that the new, substituted partial esters of methylenebisphosphonic acids and their salts in many cases exhibit more favorable properties than the corresponding bisphosphonic acids and salts due to their better kinetics and availability, which supports their ability to participate in the metabolism of the organism.

They are well suited for the treatment of disorders related to the metabolism of calcium and other metals, especially divalent metals. They can be used both in the treatment of skeletal diseases such as osteoporosis and Paget's disease and in the treatment of soft tissue diseases such as deposition and mineralization disorders and bone formation.

On the other hand, as pyrophosphate analogs, the new substituted methylenebisphosphonic acid derivatives are also suitable for the treatment of disorders of (pyro) phosphate function in the body, including functions in which an active but susceptible or malfunctioning organic part is coupled to (pyro) phosphate or acts as a metal complex or in a combination of the mentioned cases.

The new bisphosphonates regulate the quality and level of cations and / or pyrophosphate compounds free in body fluids as well as bound, active in tissues and released from tissues through a direct or indirect mechanism. They are therefore capable of regulating cell metabolism, growth and destruction. Consequently, they have applications in the treatment of, for example, bone cancer and its metastases, ectopic calcifications, urolithiasis, rheumatoid arthritis, bone infractions and bone degradation.

Typical of the novel substituted methylene bisphosphonates is the selective, desired and controlled action ensuring a better therapeutic index.

The method according to the invention produces new methylenebisphosphonic acid derivatives of the general formula 1

169 796 wherein R ¹ R ² R ³ and R ⁴ independently represent straight or branched, optionally unsaturated C 1 -C 1 -alkyl, optionally unsaturated C 3 -C 10 -cycloalkyl, aryl, aralkyl, silyl S ¹ R ³ or a hydrogen atom with at least one of the groups R R 2 R ³ and R ⁴ is hydrogen and at least one of Ri R2 ^R3 and R is other than hydrogen, Qi is hydrogen, hydroxy, halogen, amino NH2, or a group oR 1, wherein R is Ci-C * alkyl or acyl, ^Q2 is a group of formula

R '

R "wherein Y is an optionally substituted, saturated, partially saturated or aromatic six-membered heterocycle or carbocyclic aromatic group, the heterocyclic group may contain and up to 3 atoms selected from the group consisting of N, O and S atoms, X is a bond, O, S or NR ', where R' is hydrogen, C1-C4 lower alkyl or acyl, n is an integer from 0 to 6, and R 'and R are independently hydrogen or C1-C4 lower alkyl, with as a Y ring atom and / or a chain atom of the X group always contain at least one heteroatom from the O, N and S group, provided that when Qi is OH then Q2 is not phenoxymethyl and Ri and R3 are other than ethyl, including stereoisomers such as geometric isomers and optically active isomers, as well as the pharmacologically acceptable salts of these compounds.

The groups R 1 R ² R ³ and R ⁴ independently represent straight or branched alkyl, alkenyl or alkynyl and contain from and to 10, or from 2 to 10, respectively, carbon atoms, preferably from 1 to 7, or 2 to 7 carbon atoms, preferably from i to 4 or 2 to 4 carbon atoms.

Optionally unsaturated cycloalkyl is cycloalkyl or cycloalkenyl having from 3 to 10 carbon atoms, however preferably cyclopropyl, -butyl, -pentyl or -hexyl.

Aryl or aralkyl as the group R 2 R ³ R and R is an optionally Ci-C4 lower-alkyl, lower-Ci-C4-alkoxy or halogen substituted monocyclic aryl or aralkyl, such as phenyl or benzyl, preferably, however, unsubstituted phenyl or benzyl.

Halogen is a fluorine, chlorine, bromine or iodine atom.

The acyl group is alkyl-, aryl- or aralkylcarbonyl, or alkoxy-, aryloxy- or aralkoxycarbonyl, wherein the alkyl contains from and to 4 carbon atoms and aryl and aralkyl are as defined above.

In the silyl group of SiR3, the R group is lower alkyl having from and to 4 C atoms, especially methyl, ethyl, isopropyl, butyl, t-butyl or it is phenyl or R-substituted phenyl, various combinations of lower alkyl groups and phenyl compounds such as dimethyl t-butyl, methyl diisopropyl, dimethyl phenyl, diethyl phenyl, methyl t-butyl phenyl, diisopropyl- (2,6-dimethylphenyl).

As heteroaromatic and saturated heterocyclic Y groups, there may be mentioned, respectively, six-membered unsaturated ring groups containing nitrogen, oxygen and / or sulfur, such as pyridine, pyrimidines, pyrazines, pyradines, oxazines, thiazines, triazines, as well as corresponding saturated groups such as piperidine groups , piperazine, morpholine, oxathate, dithian, thiomorpholine, etc. Heterocyclic groups may be substituted as described below for aryl and aralkyl groups.

The Y group as a carbocyclic aromatic group is a substituted or unsubstituted aromatic ring, such as a monocyclic aryl or aralkyl, especially phenyl, or a conjugated or bridged unsaturated or partially saturated ring system such as naphthyl, phenanthryl, indenyl, indanyl, tetrahydronaphthyl, biphenyl, di- and triphenylmethyl, etc.

Monocyclic aryl or aralkyl may be represented by the formula

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wherein the D 'groups are independently C1-C4-alkyl or alkoxy, halogen or nitro, m' is. an integer from 0 to 1 and D is straight or branched C1-C6-alkylene, -alkenylene or -alkynylene. Halogen is a fluorine, chlorine, bromine or iodine atom.

The group Y-X in formula 1 contains at least one heteroatom from the group O, N and S as a ring atom in Y and / or as a chain atom in X.

The salts of the compounds of formula I are in particular their salts with pharmaceutically acceptable bases, such as metal salts, for example alkali metal salts, especially lithium, sodium and potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, copper, aluminum or zinc, as well as ammonium salts with ammonia or with primary, secondary or tertiary amines, both aliphatic and alicycic, as well as with aromatic amines and quaternary ammonium salts such as halides, sulfates and hydroxides, salts with amino alcohols such as ethanol, diethanol and and triethanolamines, tris (hydroxymethyl) aminomethane, 1- and 2-methyl and 1,1-, 1,2- and 2,2-dimethylaminoethanols, N-mono and N, N-dialkylaminoethanols, N-i hydroxymethyl and ethyl) - N, N-ethanediamines, as well as amino substituted crown ethers and cryptands and heterocyclic ammonium salts such as azetidinium, pyrrolidinium, piperidinium, piperazine, morpholine, pyrrolyl, imidazolyl, pi ryidinium, pyrimidinium, quinohnium, etc.

Good results have been obtained with the following mono- or dimethyl-, mono- or diethyl-, mono- or diisopropyl esters in which Q ^! is hydrogen and Y is a heterocyclic group such as unsubstituted or methyl substituted pyridine or piperidine, n is O and X is NH or S, and particularly good results have been obtained with the following compounds:

[[(6-Methyl-2-pyridinyl) amino] methylidene] bisphosphate P, P'-dielyl ester; :) new, [[(2-pyridinyl) amino] methylene] bisphosphonic acid P, P'-diethyl ester, [[(2-Pyridinyl) amino] methylidene] bisphosphonic acid P, P-methyl ester, [[(3-Methyl-2-plridinyl) amino] meiylidene] bisphosphonic acid P, P'-diethyl ester, P, P 'ester [[(4-Methyl-2-pyridinyl) amino] methylldene] bisphosphonic acid diethyl ester, [[(2-pyridinyl) thio] methylde] bisphosphonic acid monoisopropyl ester, [[(4-chlorophenyl) thio acid P, P'-dimethyl ester ] methylidene] bisphosphonic acid, [[(6-methyl-2-pyridinyl) amino] methylldene] bisphosphonic acid monoethyl ester, [[(3-methyl-2-pyridinyl) ammo] methyhdenum] bisphosphonic acid monoethyl ester, [[(3-methyl-2-pyridinyl) ammo] bisphosphonic acid monoisopropyl ester, 1-Hydroxy-2- (3-plridinyl)] ethylIdeno] bisphosphonic acid, [[1-hydroxy-2- (3-pyridinyl)] ethylidene) bsphosphonic acid monoisopropyl ester, [[2- (3 -pyridinyl)] ethylidene] bisphosphonic acid, monomethyl acid [[2- (3-pyrid ynyl)] ethylidene] bisphosphonic acid, P, P'-dimethyl ester of [[(3-plrid; ^ m2 ^^lo) a ^^ l ^ o] m ^ 'iylI <dt ^ I ^ o] l ^ l ^ fc ^^ ίf ^) ^ <^ 'wego, P, P'-diethyl ester of [[(3-pyr ^^^; ^ l ^ o) t ^ o] met ^: ^ i ^ (^^: and [[(4-Pyridinyl) thio] methylidene] bisphosphonic acid, monoisopropyl ester of [[(3-pyrrole]), P, P'-diethyl ester ^; ^ lo) t ^ o] met ^ l ^! ^^ i ^ o] bi! ^ lfo! ^: foi ^ «^ 'wego.

The method of producing compounds of formula 1 consists in the fact that methylenebisphosphonic acid tetraester of formula 2 θ _OR 1

OR '

OR

169 796 where Q ^! and Q ² are as defined above and R ¹ R ² R ³ and R ⁴ are as defined above except for hydrogen, are selectively hydrolyzed to a triester of formula I, in which one of the groups R 1 R ² R ³ and R 4 is hydrogen or a salt thereof, or to a diester of the formula 1 in which two of the groups R 1, R 2 R ³ and R 4 are hydrogen or a salt thereof, or to a monoester of the formula 1 in which three of the groups R 1, R 2 R ³ and R ⁴ are hydrogen or a salt thereof, and if necessary, the obtained partial ester acid is converted into partial ester salt, or the obtained partial ester salt is converted into partial ester acid, and / or, if necessary, the obtained compound of formula I is converted into another compound of of formula 1 by hydrolysis.

Preferably, for the preparation of a compound of formula 1 wherein Q1 is hydrogen, Y is unsubstituted or methyl substituted pyridine or piperidine, n is O and X is NH or S, R1 is methyl, ethyl or isopropyl, R2 and R3 are hydrogen or one of R2 and R3 may be methyl, ethyl or isopropyl and R4 is hydrogen, the compound of formula 2 wherein Q ', Y, n, X and R ¹ are as defined above, and R 2 R ³ and R ⁴ are methyl, ethyl, isopropyl or lower trialkylsilyl, R ⁴ and any lower trialkylsilyl present and optionally also one or both of R 2 and R 3 are hydrolyzed.

Thus, the compounds of formula 1 are prepared by selective hydrolysis of the tetraesters of the formula 2. The starting material is therefore tetraester, wherein R1 R2 ^R3 and R4 and Q1 and Q2 are as defined above and this tetraester is hydrolyzed gradually to a triester of formula 3, a diester of formulas 4 and 5, and a monoester of formula 6. If desired, the partial ester or a salt thereof can be isolated and purified by extraction, fractional crystallization or chromatography, and if desired, the free acid can be salified or salified into the free acid.

This reaction is shown in the diagram below (the reaction takes place in the direction of the upper arrow).

Scheme

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Hydrolysis of the tetraesters of formula II can be accomplished by both acid and base treatment, by thermal cleavage, and in some cases also by water, alcohols, or neutral or non-neutral transalkylation, -silylation and -arylation reagents. Preferably, the hydrolysis takes place at a temperature of 10-150 ° C. The acids used are preferably conventional inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and Lewis acids such as boron trifluoride etherate, ritanium tetrachloride, etc., as well as many organic acids such as oxalic acid, formic acid, acid acetic and other carboxylic acids, methanesulfonic acid and other sulfonic acids such as tosic acid, then fluorine and chlorine substituted carboxylic acids and sulfonic acids such as trifluoro acetic acid and trifluoromethanesulfonic acid and aqueous solutions thereof.

Preference is given to using alkali metal and ammonium hydroxides and ammonia and their aqueous solutions as bases, as well as many amines such as primary, long-order and tertiary amines, such as, for example, diethyl-, tr-, 3-, butyl, diisopropyl and tributylamine, aniline. , N- and N, N-alkyl substituted anilines and heterocyclic amines such as pyridine, morpholine, piperidine, piperazine, etc. and hydrazines such as N, N-dimethylhydrazine.

In addition, acids and bases bound to a solid support such as Amberlites can be used either in the presence of an organic solvent or water or various mixtures of solvents, or in the absence thereof.

Besides, by treatment with certain alkali metals such as sodium and lithium or with suitable inorganic salts such as sodium iodide, lithium bromide, ammonium chloride and NaBr / PTC, the ester group can be converted into the corresponding salt such as sodium, ammonium and lithium salt .

Thermal cleavage usually takes place at a temperature of about 100 to 400 ° C, usually, however, at a temperature of not more than 250 ° C. The presence of a suitable catalyst such as an acid or an acid solution or a quaternary ammonium salt allows the reaction to be carried out faster and at a lower temperature. Some active substituents, such as benzyl or allyl, can be removed by catalytic or electrolytic reduction.

Inert organic solvents such as hydrocarbons, lower alcohols and stable ketones and esters, alkyl halides such as chloroform, dichloromethane and -ethane, ethers such as dioxane, dimethoxyethane, can be used as co-solvents to improve solubility and control the temperature during the reaction. diglym, acetonitrile, etc.

When the groups R 1 to R 4 in the tetraester of formula II are the same, the hydrolysis is gradual and is stopped when the concentration of the desired partial ester is at its highest.

In order to obtain a particular partial ester structure, it is desirable to use a tetraester of formula II in which the ester groups are not the same but differ with respect to the rate of hydrolysis. For example, the rate of hydrolysis of alkyl and silyl esters was found to be structure dependent as follows:

silil> tert> sec> prim

It is possible to influence the rate of hydrolysis by changing the size and shape of the alkyl and silyl substituents as well as by electronic factors. It is often possible to carry out transesterification to alter the gradual hydrolysis of various ester sites. Especially the methyl ester can advantageously be converted into the corresponding acid via the Sihl ester.

Thus, pure partial esters are preferably prepared by selective hydrolysis of mixed esters of formula I, which have been obtained with the preferred ester groups from the point of view of hydrolysis.

Other selective hydrolysis reactions, particularly known in the chemistry of phosphates and monophosphonates, can also be used.

The progress of the hydrolysis can be followed, for example, by chromatography or by means of 3'P-NMR spectroscopy. The reaction can be stopped when the level of the desired partial ester is at its highest and the product can be recovered from the reaction mixture either as free.

Acid, either as a salt by precipitation, extraction or chromatography, and the salt may be converted to the free acid or the free acid may be converted to its salt.

The tetraesters of formula 2 used as starting compounds in the process according to the invention can be obtained by methods known from the literature by constructing a PCP structure from parts thereof, for example using the Michealis-Becker, Michealis-Arbuzov reactions or the carbanion reaction, also stepwise, with R 'to R ⁴ may be selected and preferably introduced as the bisphosphonate part taking into account the structure of the desired partial ester and by suitable substitution of this structure or an anion derived therefrom, for example by an alkylation or addition reaction.

N-substituted (aminomethylidene) bisphosphonic acid tetraesters can be obtained by reacting an amino substituted compound with an alkyl orthoformate and reacting an iminester derivative obtained as an intermediate with dialkyl phosphite either as such or in a purified form.

N-substituted (aminomethylidene) bisphosphonic acid esters can also be obtained by reaction between alkenyl bisphosphonic acid esters and amine derivatives or by appropriate substitution of (alkylidene) bisphosphonic acid esters.

The Q-substituted tetraesters of the acid (oxyalkyl and ^ i ^^ I ^ <) bi ^ lpho ^ ^^^ can be obtained, for example, by reacting the corresponding dichloroalkyl esters with dialkyl phosphites and by reacting the thus obtained (chloroalkoxymethyljiphosphonates with salt sodium dialkyl phosphite.

(Thiomethylidene) bisphosphonates can be obtained by reacting a disulfide and a methylene bisphosphonate anion.

With regard to the formation of the desired partial esters, the obtained tetraesters can, if necessary, be converted into other suitable tetraesters by exchange reaction. In these reactions, the OR 'to OR4 groups may be exchanged directly or through the appropriate phosphonochloride or using other known methods.

Optically active partial esters can best be prepared using the above-mentioned starting compounds, intermediates and end products, or by exchange reactions of known optically active compounds such as optically active alcohols.

The properties of the compounds according to the invention were tested in the following test systems.

The activity of the compounds in inhibiting parathyroid hormone-stimulated bone resorption in the cranial vault of mice in vitro was determined as well as in inhibiting retinoid-induced bone resorption in rats after thyroidectomy [Reynolds and Dingle (Cals Tiss Res 1970; 4: 339 and Trechsel et al. Clin Invest 1987; 80: 1679)].

Table

Anti-resorptive activity

Relationship Inhibition of resorption (%) 100 pm in vitro 150 praols / kg in vivo Clodronate 43 64 [[(3-methyl-2-pyridinyl) amino] methylidene] bisphosphonate 51 WELL [[(2-Pyridinyl) amino] methylidene] bisphosphonate 56 > 100 P, P-diethyl [[(3-methyl-2-pyridinyl) amino] methylidene] bsphosphate 43 66 P, P-ώethyl [[(2-pirld3nló) aminó) methylidene] bitfóbf] orιιian of PJP-diethyl 33 65 [[(1-pyridinyljthioimethylidenolbisfbsfoniari monoisopropyl 50 87

NO = not determined

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The table shows the excellent activity of the compounds according to the invention, especially their better relative anti-resorptive activity in vivo, considering that they do not bind to hydroxyapatite, although they inhibit crystal growth. They provide a better therapeutic index with fewer side effects.

Partial esters of substituted bisphosphonic acids of formula I can be used as pharmaceuticals as such or in the form of pharmaceutically acceptable salts, such as alkali metal or ammonium salts. Such salts can be prepared by reacting the ester acids with the appropriate inorganic or organic bases. Depending on the reaction conditions, ester salts can also be prepared directly in the above-mentioned reactions.

The novel compounds of formula I can be administered enterally or parenterally. All known administration forms can be used, such as tablets, capsules, granules, syrups, solutions, implants and suspensions. All formulation, dissolution and administration aids as well as stabilizers, viscosity-regulating and dispersing agents and buffers can also be used.

Such auxiliaries include, but are not limited to, tartrate and citrate buffers, alcohols, EDTA and other non-toxic complexing agents, solid and liquid polymers and other sterile media, starch, lactose, mannitol, methylcellulose, talc, silicic acids, fatty acids, gelatin, agar- agar, calcium phosphate, magnesium stearate, animal and plant fats and, if desired, flavors and sweeteners.

The dosage depends on several factors, for example the mode of administration, the subject, age, and individual condition. The daily dose is about 0.1 to 1000 mg, usually

1-100 mg per person and can be administered as a single dose or in divided doses.

For medical use, preparations for intramuscular or parenteral administration, for example an infusion concentrate, can also be prepared, for example, sterile water, phosphate buffer, NaCl, NaOH or NaHCl, or other known pharmaceutical adjuvants suitable for this purpose, can be used as adjuvants.

The compounds of formula I in their ester-acid form are waxy liquids or substances, usually soluble in organic solvents and, in some cases, in water. Ester salts are solid, crystalline and typically powdery substances which usually dissolve well in water, in some cases in organic solvents, but only some structures are poorly soluble in all solvents. The compounds are very stable, also in solutions that are neutral at room temperature.

The structure of the compounds may easily be verified by spectroscopy 1 H, ¹³ C and 3'f NMR and FAB mass spectrometry or sibilowaniu using s ^ p ^ e ^ Lat ^ r ^ c ^^ kropiii EI mass. 3P-NMR spectroscopy (85% H3PO4, δ = 0) is very suitable for the determination of concentration and impurities. Ion exchange and exclusion HPLC can also be used for polar compounds, and gas-liquid chromatography and gas chromatography coupled with mass spectrometry for tetraesters and silicate derivatives of acid esters.

The Examples which follow illustrate the invention, with Examples 1-3 being the preparation of the starting compounds.

Example I. Preparation of [[(3-methyl-2-pridinyl) amino] methylidene] bisphosphonic acid tetraethyl ester.

A mixture of 2-a.mlnc-3-methylpyridine (0.2 mol), triethyl orthoformate (0.24 mol) and diethyl phosphate (0.42 mol) was heated at 150 ° C for 30 minutes and then the formed in ethanol reaction. The mixture was cooled and the crude product was purified by chromatography (eluent methanol-dichloromethane, 1: 1). Yield 37 g (49%; 31-P-NMR 18.86 ppm; CDCl ₃ ).

The following starting materials were prepared in a similar manner.

[[(4-Methylc-2-pithidinyl) amino] methylene] bisphosphonic acid tetraethyl ester from 2-amino-4-methyl-pyridine (31-P NMR 18.60 ppm; CDCl3).

[[(6-Methylc-2-pithidinyl) amino] methylene] bisphosphonic acid tetraethyl ester from 2-ammo-6-methylpnydine (31-P NMR 18.75 ppm; CDCl ₃ ).

I69 796 ii

[[(2-Pyridinyl) amino] methylene] bisphosphonic acid tetraethyl ester from 2-aminopyridine (3i-P NMR and 8.62 ppm; CDCl ₃ ).

[[(3-Pyridinyl) amino] methylidene] bisphosphonic acid tetraethyl ester from 3-aminopyridine.

[[(3-Pyridinyl) amino] methylidene] bisphosphonic acid tetrazopropyl ester from 3-methylpyridine.

[[(2-Pyridinyl) amino] methylidene] bisphosphonic acid tetramethyl ester from 2-aminopyridine (3i-P NMR I 6.00 ppm; CDCl ₃ ).

[[(4-Pyridinyl) amino] methylidene] bisphosphonic acid tetraethyl ester from 4-aminopyridine.

[[(3-Hydroxy-2-pyridinyl) amino] methylidene] bisphosphonic acid tetraethyl ester (3i-P NMR i 8.76 ppm; CDCl ₃ ).

[[(4-Methoxy-3-pyridinyl) amino] methylidene] bisphosphonic acid tetraethyl ester (3i-P NMR I8, 1.5 ppm; CDCl ₃ ).

[[(4,6-Dihydroxy-2-pyridinyl) amino] methylidene] bisphosphonic acid tetraethyl ester.

Example II. Preparation of [i-hydroxy-2- (2-pyridinyl) ethylidene] bisphosphonic acid tetramethyl ester.

To a chloroform solution of trimethyl phosphite (0.1 mol) and dimethyl phosphite (0.1 mol) was slowly added at 0 ° C (2-pyridinyl) acetyl chloride (0.1 mol) dissolved in chloroform. The mixture was heated at 80 ° C for 10 hours. The solvent was evaporated under reduced pressure and the product was purified by partition chromatography (eluent methylene chloride - methanol and: i). Yield 4 g (4%).

The following starting materials were prepared in a similar manner from the corresponding compounds by proceeding as described above.

[I-Hydroxy-2- (3-pyridinyl) ethylidene] bisphosphonic acid tetrazopropyl ester (3i-P NMR 20.02 ppm; CDCl ₃ ).

[I-Hydroxy-2- (4-pyridinyl) ethylidene] bisphosphonic acid tetraisopropyl ester.

Example III. Preparation of [[2- (2-pyridinyl) ethylidene] bisphosphonic acid tetrazopropitic ester.

Sodium hydride (0.15 mol) in dry toluene was suspended under nitrogen and tetraisopropyl methylene phosphonate (0.065 mol) was slowly added. The solution was stirred until hydrogen evolution ceased. 2-picolyl chloride (0.72 mol) dissolved in dimethylformamide was added slowly and the solution was heated to reflux for 12 hours. The solvent was evaporated and the product was purified by partition chromatography (eluent toluene - acetone, and: i). Yield 58%.

The following starting materials were prepared in a similar manner from the corresponding compounds by proceeding as described above:

[[(2-Pyridinyl) thio] methylidene] bisphosphonic acid tetramethyl ester from 2,2'-dipyrinyl disulfide (3i-P NMR 23.26 ppm; CDCl3).

[2- (3-Pyridinyl) ethylidene] bisphosphonic acid tetrazopropyl ester (3I-P NMR 20.13 ppm; CDCb).

[[(2-Pyridinyl) thio] methylidene] bisphosphonic acid tetrazopropyl ester from 2,2'-dipyridyl disulfide (3I-P NMR i 8.85 ppm; CDCl 3).

[2- (3-Pyridinyl) ethylidene] bisphosphonic acid tetraethyl ester (3I-P NMR 22.00 ppm; CDCl 3).

[[(3-Pyridinyl) thio] methylidene] bisphosphonic acid tetrazopropyl ester from 3,3'-dipllydisulfide, 3, 4-yl disulfide.

[[(4-Pyridinyl) thio] methylidene] bisphosphonic acid tetraethyl ester from 4,4'-dipyridine disulfide.

[[(2-Pyridinyl) thio] ethylidene] bisphosphonic acid tetraethyl ester from 2,2'-diphyla disulfide.

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[[(2-Pyridinyl) thio] methylidene] bisphosphonic acid isopropyl ester, trimethyl ester from 2,2'-dipyridinyl disulphide and isopropyl methylenebisphosphonate and tetyl isopropyl (31-P NMR 20.21 / 17, 5 ppm; CDCl ₃ ).

[[(4-Chlorophenyl) thio] methylidene] bisphosphonic acid tetraisopropyl ester from bis (4-chlorophenyl) disulfide (31-P NMR 18.14 ppm; CDCl ₃ ).

[[(4-Chlorophenyl) thio] methylidene] bisphosphonic acid tetraethyl ester from bis (4-chlorophenyl) disulfide.

[2- (2-Pyridinyl) ethylidene] bisphosphonic acid P, P'-dimethyl P, P'-diisopropyl ester from 2-picolyl chloride and P, P'-dimethyl P, P'-diisopropyl methylene bisphosphonate.

[2- (3-Pyridinyl) ethylidene] bisphosphonic acid P, P'-dimethyl ester of [2- (3-Pyridinyl) ethylidene] bisphosphonic acid from 3-picolyl chloride and P, P'-dimethyl P, P'-d-tisopropyl methylene bisphosphonate.

[2- (4-Pyridinyl) ethylidene-ebisphosphonic acid tetraethyl ester from 2-picolyl chloride.

Additionally, by using sodium diisopropylamide as base, one can obtain:

[[(4-Chlorophenyl) thio] methylidene] bisphosphonic acid P, P'-dimethyl P, P'-bis (trimethylsilyl) ester.

[2- (2-Pyridinyl) ethylidene] bisphosphonic acid P-ethyl P, P'P'-bis (trimethylsilyl) ester.

[2- (3-Pyridinyl) ethylidene] bisphosphonic acid P-methyl P, P'P'-trls (trimethylsilyl) ester.

[[(4-Chlorophenyl) thio] methylidene] bisphonic acid P-ethyl P, P'P'-tπs (thiemethylsilyl) ester.

Example IV. Preparation of [[(6-Methyl-2-pyridinyl) amino] methylidene] bisphosphonic acid P, P'-diethyl ester.

Chlorotrimethylsilane (0.042 mol) was added slowly at room temperature to a solution of [(6-methyl-2-pyridinyl) amino] methylidene bisphosphonic acid tetraethyl ester (0.02 mol) and sodium iodide (0.04 mol) in acetonitrile. The solution was stirred slowly for 3 hours then the solvent was evaporated under reduced pressure. The evaporation residue was dissolved in a little warm water and the solution was made basic with a dilute sodium hydroxide solution. The product was precipitated by adding ethanol (31-P NMR 11.34 / 22.79 ppm, J = 34.3 Hz; D ₂ O).

The following esters and their sodium salts were prepared in a similar manner;

[[(2-Pyridinyl) tto] methyldene] bisphosphonic acid P, P-diisopropyl ester from the corresponding tetrazopropyl ester (31-P NMR 9.34 / 20.44 ppm, J = 14.9 Hz; D ₂ O).

[[(2-Pyridinyl) thio] methylldene-ebisphosphonic acid P, P-diethyl ester from the corresponding tetraethyl ester.

[[(3-Pyridinyl) tto] methyldene] bisphosphonic acid P, P-diisopropyl ester from the corresponding powdery tetrazopropyl ester.

[[(2-Pyridinyl) is] Ethylene-Ebisphosphonic acid P, P-diethyl ester from the corresponding tetraethyl ester.

[2- (2-Pyridinyl) ethylene-ebisphosphonic acid P ', P'-diisopropyl ester from the corresponding P, P-dimethyl P', P'-diisopropyl ester.

[2- (3-Pyridinyl) -1-hydroxyethylidene] bisphosphonic acid P ', P'-diethyl ester from the corresponding PyP-diethyl P, P-dimethyl ester.

[[(4-Chlorophenyl) thio] methylene] bisphosphonic acid P, P-diisopropyl ester from the corresponding tetropropyl ester (31-P NMR 10.84 / 21.38 ppm; J = 15.2 Hz; D ₂ O).

[[(6-Methyl-2-pyridinyl) ammino] methylldene] bisphosphonic acid P, P-diethyl ester from the corresponding tetraethyl ester (31-P NMR 11.3-4 / 22.79 ppm; J = 34.3 Hz; D ₂ O).

[[(4-Methyl-2-pyridinyl) amino] methylidene] bisphosphonic acid P, P-diethyl ester (31-P NMR 11.43 / 22.83 ppm; J = 35.0 Hz; D ₂ O) from the corresponding [[(4-Methyl-2-pyridinyl) amino] methylidene] bisphosphonic acid tetraethyl ester.

[2- (3-PyridinJ ^^ ιe) et ^ lιi ^^ r ^ oel ^ l ^ fc ^^ f <^ e ^ <^ 'oic acid P, P-diethyl ester from the corresponding tetraethyl ester.

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[(3-Pyridinylamino) methylidene] bisphosphonic acid P, P-diethyl ester from the corresponding tetraethyl ester.

Example 5 Preparation of [[(4-chlorophenyl) thio] methylidene] bisphosphonic acid monoisopropyl ester and its trisodium salt.

[[(4-Chlorophenyl) thio] melylidene] bisphosphic acid tetraisopropyl ester (0.02 mol) was dissolved in dichloromethane and bromotrimethylsilane (0.062 mol) was added slowly to the solution at room temperature. The solution was stirred at room temperature for 3 hours and the solvent was evaporated under reduced pressure. The evaporation residue was dissolved in a little water and the solution was made basic with a dilute sodium hydroxide solution. The product was precipitated by adding ethanol (31-P nMr 12.21 / 18.25 ppm; J = 9.8 Hz; D ₂ O).

Example VI. Preparation of [[(2-pyridyl) thio] methylidene] bisphosphine acid tetrasopropyl ester and its sodium salt.

[[(2-Pyridyl) thio] methylidene] bisphosphonic acid tetraisopropyl ester (0.02 mol) was dissolved in acetonitrile, and chlorofert-butyl / dimethyl-ylane (0.022 mol), dissolved in acetonitrile, was added slowly to the solution. The solution was stirred for 4 hours at 60 ° C. The solvent was evaporated and the evaporation residue was dissolved in a little water. The solution was basified with a dilute sodium hydroxide solution and the product was precipitated by adding ethanol (31-P NMR 7.78 / 23.6 ppm, J = 9.6 Hz; D ₂ O).

In a similar manner, the following compounds were prepared by using bromotrimethylsilane (1 eq) in place of chloro (tert-butyl / dimethyl) silane for example:

[2- (2-Pyridinyl) ethylidene] bisphosphonic acid trimethyl ester from the corresponding tetramethyl ester.

[2- (3-Pyridinyl) ethylidene] bisphosphonic acid trimethyl ester from the corresponding tetraethyl ester.

[[(3-Pyridinyl) thio] methylidene] bisphosphonic acid trimethyl ester from the corresponding tetraethyl ester.

[[(2-Pyridinyl) yl] methylidene] b-phosphonic acid dimethyl isopropyl ester from the corresponding isopropyl methyl ester.

[2- (3-p> Iridine; ^^ «ó) et; yli ^ (^^: n <[] bi ^ f ^^^ 1fó ^ <tory acid triisopropyl ester (31-P NMR 26.33 (15.09 ppm; CDClj).

[[(4-Methyl-2-pyridinyl) amino] methylidene] bisphosphonic acid trimethyl ester from the corresponding tetraethyl ester (31-P NmR 8.62 / 26.15 ppm; J = 25.4 Hz, D ₂ O) .

[1-Hydroxy-2- (3-pyridinyl) ethylidene] bisphosphonic acid triisopropyl ester from the corresponding tetr & L-isopropyl ester.

Example VII. Preparation of [[(3-Methyl-2-pyridinyl) amino] methylidene] bsphosphonic acid ester P, P, P, D, m, p.

[[(3-Methyl-2-plridinyl) amino] methylidene] bisphosphonic acid tetraethyl ester (0.015 mol) was dissolved in aqueous ethanol and concentrated sodium hydroxide solution (0.05 mol) was added to the solution. The solution was stirred overnight. The solvent was evaporated and the evaporation residue was mixed with ethanol. The product was filtered and dried (31-P NMR 16.60 ppm; D ₂ O).

In a similar manner, the corresponding compounds were prepared by proceeding as described above:

[[(2-Pyridinyl) amino] methylidene] bisphosphonic acid P, P-diethyl ester (31-P NMR 16.37 ppm; D ₂ O) from [[(2-Pyridinyl) amino] methylidene] bisphosphonic acid tetraethyl ester.

[[(4-Pyridinyl) amino] methylidene] bisphosphonic acid P, P'-diethyl ester.

[[(4-Chlorophenyio) thio] methylidene] bisphosphonic acid P, P'-drisopropyl ester from the corresponding tetruisopropyl ester (31-P NMR 14.00 ppm; D ₂ O).

[2- (2-Pyridinyl) ethylidene] bisphosphonic acid P, P'-diisopropyl ester from the corresponding tetraisopropyl ester.

[2- (3-Pyridinyl) ethylidene] bisphbnic acid P, P'-diethyl ester from the corresponding tetrahylayl ester.

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[1-Hydroxy-2- (2-pyridinyl) ethylidene] bisphosphonic acid P, P'-diethyl ester from the corresponding tetramethyl ester.

[1-Hydroxy-2- (3-pyridinyl) ethylene] bisphosphonic acid P, P'-diethyl ester from the corresponding tetraethyl ester.

[[(2-Hydroxy-3-pyridinyl) amino] methylidene] bisphosphonic acid P, P'-diethyl ester from the corresponding tetraethyl ester.

[[(2-Methoxy-3-pyridinyl) amino] methylidene] bisphosphonic acid P, P'-diethyl ester from the corresponding tetraethyl ester.

[[(4,6-Dihydroxy-2-pyrimidyl) amino] methylidene] bisphosphonic acid P, P'-diethyl ester from the corresponding tetraethyl ester.

Example VIII. Preparation of [[(6-methyl-2-pyridinyl) amino] methylene] bisphosphonic acid P, P'-diethyl ester and its disodium salt.

[[(6-Methyl-2-pyridinyl) amino] methylidene] bisphosphonic acid tetraethyl ester (0.009 mol) was dissolved in a mixture of morpholine (40 ml) and dichloromethane (50 ml). The solution was stirred for a day. The solvent was evaporated and the morpholine salt of the product was dissolved in acetone. Sodium hydroxide solution (0.02 mol) was added to the solution and the product precipitated as the disodium salt (31-P NMR 16.45 ppm; D ₂ O).

In a similar manner, using for example piperidine, 2-methylpiperidine or 4-benzyl-piperazine in place of morpholine,

[[(4-Plridinyl) amino] methylidene] bisphosphonic acid P, P'-dimethyl ester.

[[[1 -Pyridinyl] thio] methylldene bisphosphonic acid P, P'-diethyl ester.

[[(3-Pyridinyl) amino] methylene] bisphosphonic acid P, P'-dimethyl ester.

[2- (2-Pyridinyl) methylene] bisphosphonic acid P, P'-dimethyl ester.

Example IX. Preparation of [[(4-Methyl-2-pyridinyl) amino] methylidene] bisphosphonic acid [beta] -dietic acid ester and its disodium salt.

[[[N-Methyl-4-pyridinyl] aminomethylldene bisphosphonic acid tetraethyl ester (0.02 mol) was dissolved in dichloromethane and bromotrimethylsilane (0.042 mol) was added slowly to the solution at room temperature. The solution was stirred for 3 hours. The solvent was evaporated under reduced pressure. Sodium hydroxide solution (0.04 mol) and an equal volume of ethanol were added to the evaporation residue and the product precipitated as the disodium salt (31-P NMR 16.39 ppm; D ₂ O).

In a similar manner, the corresponding compounds were prepared by proceeding as described above:

[2- (2-Pyridinyl) ethylidene] bisphosphonic acid P, P'-diisopropyl ester from the corresponding tetraisopropyl ester.

[[(4-Chlorophenyl) thio] methylidene] bisphosphonic acid P, P'-dimethyl ester from the corresponding tetramethyl ester.

[[(2-Plridinyl) tto] methylene bisphosphonic acid P, P'-dimethyl ester from the corresponding tetramethyl ester.

[2- (2-Pyridinyl) yl] methylidene] bisphosphonic acid P, P'-diisopropyl ester from the corresponding P, P-dimethyl P ', P'-diisopropyl ester.

[[(3-Plridinyl) thio] methylene] bisphosphonic acid P, P'-dimethyl ester from the corresponding tetramethyl ester.

[2- (3-Pyridinyl) ethylidene] bisphosphonic acid P, P'-diisopropyl ester from the corresponding P, P-dimethyl P4β-diisopropic ester.

[1-Hydroxy-2- (3-pyridinyl) ethylene] bisphosphonic acid P, P'-diisopropyl ester from the corresponding tetraisopropyl ester.

Example X. Preparation of [[(6-methyl-2-pyridinyl) amino] methylene] bisphosphonic acid monoethyl ester and its trisodium salt.

[(6-Methyl-2-pyridinyl) amino] methylidene] bisphosphonic acid P, P'-diethyl ester prepared according to Example 4, (0.01 mol) was suspended in 15% hydrochloric acid solution and the solution was stirred at 80 ° C. The progress of the reaction was followed by 3'P NMR. After completion of the reaction, the mixture was evaporated to dryness, the evaporation residue was dissolved in sodium hydroxide and the trisodium salt formed was precipitated by adding ethanol. The product was filtered off and dried (60% yield, 31-P NMR 11.73 / 19.11 ppm; J = 24.7 Hz; D2O).

Similarly, the corresponding compounds were prepared by proceeding as described above;

[1-Hydroxy-2- (2-pyridinyl) ethylidene] bisphosphonic acid monoisopropyl ester from the corresponding P, P'-diisopropyl ester.

[2- (3-Pyridinyl) ethylidene] bisphosphonic acid monoisopropyl ester (31-P NMR 18.76 / 17.45 ppm; CDCl ₅ ) from the corresponding [2- (3-pyridinyl) ethylene acid P, P'-diisopropyl ester o] bisphosphonic.

[[(2-Pyridinyl) thio] methylidene] bisphosphonic acid monoisopropyl ester from the corresponding P, P'-diisopropyl ester (31-P nMr 11.79 / 18.05 ppm; J = 9.6 Hz; D ₂ O) .

[1-Hydroxy-2- (3-pyridinyl) ethylidene] bisphosphonic acid monoisopropyl ester from the corresponding P, P'-diisopropyl ester.

[[(3-Pyridinyl) thio] methylidene] bisphosphonic acid monoisopropyl ester (31-P NMR 11.79 / 18.05 ppm; J = 9.6 Hz; D ₂ O) from the P, P'-diisopropyl ester [ [(3-pyridinyl) thio] methylidene] bisphosphonic.

[[(4. ^ ^ ^ ^ ^ ^ -Pyrid; [beta] ^ ^ o] methyl ^ <a ^ o] l ^ ii ^ and ^ &lt; &apos; &gt; tH2-pyridic acid, monomethyl ester.

[[N-Methyl-4-pyridinyl] amino] methylidene] bisphosphonic acid, monomethyl ester.

[2-Pyridinyl) ethylidene] bisphosphonic acid monoisopropyl ester.

Example XI. Preparation of the ester P, P ^^ d ^: ^ i ^ opr <^ j ^ j ^! (^ 'Acid [[(2-pyridinyl) thio] meth ^] ^ lid <^ i ^ <^]] ^ ii > sc ^: ^ fc ^ i ^ t3o ^ i ^ i ^ o.

[[(2-Pyridinyl) thio] methylidene] bisphosphonic acid tetraisopropyl ester (0.01 mol) was dissolved in acetone and sodium iodide (0.023 mol) was added to the solution. The solution was stirred at room temperature for 8 hours then filtered. The solvent was evaporated. The product was isolated from the evaporation residue as the disodium salt as described in the previous example (yield 59%, 31-P NMr 14.09 ppm, D ₂ O).

In a similar manner, the corresponding compounds were prepared by proceeding as described above:

[[(2-Pyridyl) amino] methylidene] bisphosphonic acid P, P'-dimethyl ester from the corresponding tetramethyl ester (31-P NMR).

[[(2- (3-Pyridyl) thio] methylidene] bisphosphonic acid P, P'-diisopropyl ester from the corresponding tetraisopropyl ester.

[1-Hydroxy-2- (4-pyridinyl) ethylidene] bisphosphonic acid P, P'-diethyl ester from the corresponding tetraethyl ester.

[[(2- (4-Pyridinyl) thiolmethylldene] bisphosphatic acid P, P'-diisopropyl ester from the corresponding tetraisopropyl ester.

[1-Hydroxy-2- (2-pyridyl) ethylidene] bisphosphonic acid β-diethyl ester from the corresponding tetraethyl ester.

Example XII. Preparation of [[(2-pyridinyl) thio] methylCdeno] bisSphonic acid monoisopropyl ester and its trisodium salt.

[[(2-Pyridinyl) thio] methylidene] bisphosphonic acid tetraisopropyl ester (0.01 mol) was dissolved in toluene and methanesulfonic acid (0.06 mol) was added to the solution. The solution was stirred while heating and the progress of the hydrolysis was followed by 31-P NMR. The mixture was cooled and the solvent was evaporated under reduced pressure. The evaporation residue was dissolved in dilute sodium hydroxide and the product was precipitated by adding acetone (yield 62%, 31-P NMR 11.79 / 18.05 ppm; J = 9.6 Hz; D ₂ O).

In a similar manner, the corresponding compounds were prepared by proceeding as described above:

[2- (3-Pyridinyl &gt; -1-hydroxyethylidene] bisphosphonic acid P, P'-d-n -sopropyl ester from the corresponding tetraisopropyl ester.

[2- (3-Pyrid; γ-yloy-1-hydroxyethylidene-bisphosphonic acid, monomethyl ester from the corresponding tetramethyl ester.

[2- (2-Pyridinyl} -1-hydroxyethylidene] bisphosphonic acid P, P'-diisopropyl ester from the corresponding tetraisopropyl ester

[2- (3-Pyrid) Thiyl) -ethylidene] bisphosphonic acid P, P'-diisopropyl ester from the corresponding tetraisopropyl ester.

169 796

Publishing Department of the UP RP. Circulation of 90 copies Price PLN 4.00

Claims (10)

Patent claims 1. A process for the preparation of new methylenebisphosphonic acid derivatives of the general formula I wherein R ¹ R ² R ³ and R ⁴ independently represent straight or branched, optionally unsaturated C1-C10-alkyl, optionally unsaturated C3-C10-cycloalkyl, aryl, aralkyl, silyl S1R3 or hydrogen, wherein at least one of R 1 R ² R ³ and R 4 is hydrogen and at least one of R 1 R ² R ³ and R 4 is other than hydrogen, Q1 is hydrogen, hydroxyl atom halogen, amino group NH2 or group OR1, where R1 is C1-C4-alkyl or acyl, Q2 is a group of formula R * Yx- / c / _n R wherein Y is an optionally substituted, saturated, partially saturated or aromatic six-membered heterocycle or carbocyclic aromatic group, the heterocyclic group may contain 1 to 3 atoms selected from the group consisting of N, O and S atoms, X is a bond, O, S or NR ', wherein R' is hydrogen, lower C1-C4-alkyl or acyl, n is an integer from 0 to 6, and R 'and R are independently hydrogen or lower C, _-C4-alkyl, , wherein as the ring atom of Y and / or the chain atom of the group X there is always at least one heteroatom from the group O, N and S, provided that when Q1 is OH, then Q2 is not phenoxymethyl and R1 R3 are of non-ethyl meaning, including stereoisomers such as geometric isomers and optically active isomers, as well as pharmacologically acceptable salts of these compounds, characterized in that the acid tetraester 169 796 where Q 'and Q ² are as defined above and R ¹ R ² R ³ and R ⁴ are as defined above except for the hydrogen atom, are selectively hydrolyzed to a triester of formula 1, in which one of the groups R 1 R ² R ³ and R4 is hydrogen or a salt thereof, or to a diester of the formula 1 in which two of the groups R 1 R ² R ³ and R 4 are hydrogen or a salt thereof, or to a monoester of the formula 1 in which three of the groups R 1 R 2 R ³ and R 4 are hydrogen or a salt thereof, and the obtained partial ester acids are converted into partial ester salts if necessary, or the obtained partial ester salts are converted into partial ester acids, and / or, if necessary, the obtained compound of formula 1 transformed into another compound of formula 1 by hydrolysis. 2. The method according to p. 2. The process of claim 1, wherein for the preparation of a compound of formula I wherein Q 'is hydrogen, Y is unsubstituted or methyl-substituted pyridine or piperidine, n is O and X is NH or S, R1 is methyl, ethyl or isopropyl, R2 and R3 are hydrogen, or one of R2 and R3 may be methyl, ethyl or isopropyl, and R4 is hydrogen, in the compound of formula 2, wherein Q1, Y, n, X and R1 are as defined above and R ² R ³ and R 4 are methyl, ethyl, isopropyl or lower trialkylsilyl, is hydrolysed and R ⁴ each present a lower trialkylsilyl and optionally also one or both of R2 and R3. 3. The method according to p. 6. The process of claim 1, wherein [[(6-methyl-2-pyridinyl) amino] methylidene] bisphosphonic acid P, P'-diethyl ester is selectively hydrolyzed [[(6-methyl-2-pyridinyl) tetraethyl ester ) amino] methylidene bisphosphonic acid. 4. The method according to p. The process of claim 1, wherein in the preparation of [[2-pyridine-amino-methylldene] bisphosphonic acid? -Diethyl ester, the acid tetraethyl ester [[(2-pyrid; γ ^; ^ ^ o) a; ^: ^ o] is selectively hydrolyzed. met ^ lj ^ (^ (^ i ^ o] l ^ i: ^ lphoi ^ lphoi ^ (^ 'vego. 5. The method according to p. 2. The process of claim 1, wherein [[(3-methyl-2-pyridinyl) amino] methylidene] bisphosphonic acid P, P'-diethyl ester is selectively hydrolyzed [[(3-methyl-2-pridinyl) tetraethyl ester ) amino] methylidene bisphosphonic acid. 6. The method according to p. The process of claim 1, wherein [[(4-methyl-2-pyridinyl) amino] methylidene] bisphosphonic acid P, P'-dieyl ester is selectively hydrolyzed [[(4-methyl-2-pyridinyl) acid tetraethyl ester ) amino] methylidene] bisphosphonic acid. 7. The method according to p. 6. The process of claim 1, wherein in the preparation of [(2-pyridinyl) thio] methylidene] bisphosphonic acid monoisopropyl ester, the tetraisopropyl acid [[[(2-pyrid; met ^ "l (^ (^ i ^ id] b ^, and ^^ ^ ^l? acid monohydrate. 8. The method according to p. 6. The process of claim 1, wherein [[(6-methyl-2-pyridinyl) amino] methylidene] bisphosphonic acid monoethyl ester is selectively hydrolyzed [[(6-methyl-2-pyridinyl) acid P, P'-diethyl ester ) amrno] methylidene] bisphosphonic. 9. The method according to p. The method of claim 1, characterized in that in the production of monoisopropyl acid [[2- (3-p ^ i ^ ridinyl <6)] ethyl ^ <^^ l ^ <ó] bi ^ ί ^^^ lfield ^ <^ selectively [(2- (3-pyridinyl)] ethylidene] bisphosphonic acid P, P'-diisopropyl ester is hydrolyzed. 10. The method according to p. The process of claim 1, wherein [(3-pyridinyl) thio] methylidene] bisphosphonic acid P, P'-diisopropyl ester is selectively hydrolyzed in the preparation of [(3-pyridinyl) thio] methylene] bisphosphonic acid monoisopropyl ester.